MD2B - Acute Leukemias

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Introduction

Leukemia is defined as a malignant, marrow-based neoplasm of hematopoietic or lymphoid cells. The key feature of leukemia is the presence of tumor cells circulating in the blood. Acute leukemia involves aberrant differentiation and proliferation of malignantly transformed progenitor cells, and can be rapidly fatal if untreated. The two main types of acute leukemia are named for the stem cell of origin: acute lymphoblastic leukemia (ALL)if it involves lymphocytes, and acute myeloid leukemia (AML) if it involves myelocytes. Of note, both lymphocytes and myelocytes are subtypes of white blood cells. While ALL and AML are clinically similar in that they both typically present with symptoms secondary to cytopenias (lowered cell counts), there are significant laboratory features and prognostic factors that can be used to distinguish ALL from AML and to dictate therapy, as discussed below.

Note: The characteristic presentation of T cell ALL is an older age boy with mediastinal mass and leukocytosis.

Natural Course

Staging is not clearly defined for ALL, and patients with confirmed diagnoses are grouped as:

untreated (not in remission) - defined as an abnormal white blood cell count and differential, abnormal hematocrit/hemoglobin and platelet counts, abnormal bone marrow with more than 5% blasts, and signs and symptoms of the disease.

in remission - where a patient has received remission-induction treatment and now has normocellular bone marrow with less than 5% blasts, no signs or symptoms of the disease, no signs or symptoms of central nervous system leukemia or other extramedullary infiltration, and all normal hematologic laboratory values.

recurrence – defined as any failure since starting treatment, further characterized according to time since diagnosis and relapse site (bone marrow, extramedullary)

Prognosis – grouped into low-, standard-, and high-risk; grouping schemes (particularly genetic analysis) are an area of active research [7] Worse prognoses if:

Risk assessment is critical to achieving cure with an acceptable degree of toxicity. Generally, patients with higher-risk disease receive more aggressive therapy.

High-dose chemotherapy regimens with at least two rounds of induction (prednisone or dexamethasone, vincristine, L-asparaginase, +/- an anthracycline), consolidation and maintenance.

Long-term, disease-free survival is seen in 30-40% of patients [7]

Delayed intensification was a major advance in 1983, followed by advances in bone marrow transplantation (high dose chemo +/- total body irradiation followed by marrow infusion) [9]. Allogenic transplantation is of particular benefit in high-risk disease (chromosomal translocations) and after poor response to initial therapy.

Central nervous system coverage to prevent or treat disease (intrathecal chemotherapy or irradiation) is critical for long term control

Incidence of AML is 13,000 cases per year in the US [11]. AML accounts for 80-90% of adult acute leukemias, 10% of childhood leukemias and virtually all neonatal acute leukemias.

Etiologic factors are thought to include exposure to carcinogens and mutagens, such as benzene, alkylating agents and ionizing radiation; inherited genetic conditions such as Fanconi's anemia and Down's syndrome; and viruses.

Pathogenesis involves clonal evolution through multiple steps. AML etiology and pathogenesis is considered similar to myelodysplasia, (also known as MDS, refractory anemia, preleukemia or smoldering leukemia), which is a clonal abnormality of pluripotential stem cells with defective maturation and ineffective hematopoiesis

Clinical Presentation

History: Present with cytopenia-related symptoms, as with ALL

Physical Exam: Pallor, petechiae, fever, organ involvement

Labs: Cytopenias common; consider a medical emergency if WBC count is >100,000 or there are DIC-type indices

Staging is similar to ALL in that there is no clear-cut system; patients are classified as

untreated - newly diagnosed leukemia with no prior treatment, abnormal bone marrow with more than 20% blasts, signs and symptoms of the disease, and typically abnormal hematologic cell counts

in remission - a normal peripheral blood cell count and normocellular marrow with less than 5% blasts in the marrow, no signs or symptoms of the disease, and no signs or symptoms of central nervous system leukemia or other extramedullary infiltration.

relapsed or refractory- evidence of disease as described above after achieving remission or unsuccessful treatment

Prognosis - three most important factors are age, WBC count, and cytogenetics [12]
Unfavorable prognoses [6,12,13] for patients with:

age >60 y

WBC > 30,000

CNS involvement

disease secondary to MDS, chemo or XRT

CD34 +

MDR 1-positive

Complex karyotypic abnormalities

Favorable prognosis with [12]:

t (8;21), inv(16)/t(16;16), t(15;17)

Treatment

AML chemotherapy is administered in two basic phases, induction and post-remission.

Induction with daunorubicin + anthracycline with 70-80% complete remission rate, but also 100% relapse rate if no further therapy is given [14].

Oct 8, 2010 - Postnatal diagnostic X-ray exposure may be associated with an increased risk of childhood acute lymphoid leukemia, specifically B-cell acute lymphoid leukemia, according to a study published online Oct. 1 in the International Journal of Epidemiology.